We investigate the physical principles of channel-facilitated transport of metabolites and other large solutes across cell and organelle membranes. Large ion channels are not only the gateways of metabolite exchange between different cellular compartments and cells; they are also recognized as multifunctional membrane receptors and components of many toxins. To study these channels under precisely controlled conditions, we reconstitute channel-forming proteins into planar lipid bilayers.[unreadable] [unreadable] I. Blocking anthrax lethal toxin. Bacillus anthracis secretes three polypeptides: protective antigen (PA), lethal factor (LF), and edema factor (EF), which interact at the surface of mammalian cells to form toxic complexes. LF and EF are enzymes that target substrates within the cytosol; PA provides a heptameric pore to allow LF and EF transport into the cytosol. Other than administration of antibiotics shortly after exposure, there is currently no approved effective treatment for inhalational anthrax. We demonstrate a novel approach to disabling the toxin: high-affinity blockage of the PA pore by a rationally-designed low-molecular weight compound that prevents LF and EF entry into cells. Guided by the 7-fold symmetry and predominantly negative charge of the PA pore, we synthesized small cyclic molecules of 7-fold symmetry, beta-cyclodextrins chemically modified to add seven positive charges. By channel reconstitution and high-resolution conductance recording, we show that per-6-(3-aminopropylthio)-beta-cyclodextrin interacts strongly with the PA pore lumen, blocking PA-induced transport at sub nano-molar concentrations (IC50 = 0.6 nM in 0.1 M KCl). The compound protected RAW 264.7 mouse macrophages from anthrax lethal toxin (LeTx = PA+LF) cytotoxicity. More importantly, it completely protected the highly susceptible Fischer F344 rats from LeTx. We anticipate that this approach will serve as the basis for a structure-directed drug discovery program to find new and effective treatments for anthrax.[unreadable]